Regenerative Medicine for Joint Hypermobility and Instability

Inclusion Criteria:

• Adults age 18 years or older, any gender.

• Symptomatic joint hypermobility or instability attributable to one of the following:

  1. hEDS diagnosed using the 2017 International Classification of the Ehlers-Danlos Syndromes diagnostic criteria;
  2. HSD classified using the 2017 framework (generalized, peripheral, localized, or historical HSD) with Beighton scoring; or
  3. post-traumatic joint instability with ligamentous injury documented by examination and/or imaging.

• Objective evidence of instability or clinically relevant hypermobility at one or more target joints, defined as at least one of:

  1. a positive joint-specific instability provocation test on standardized physical examination;
  2. generalized hypermobility (Beighton score ≥ 5/9 for adults) or documented joint-specific hypermobility at the target joint; or
  3. imaging evidence of ligamentous laxity or injury at the target joint (dynamic ultrasound, stress radiograph, or MRI).
• Pain attributable to the target joint for at least 3 months.
• Baseline pain score of 4 or greater on a 0-10 numeric rating scale.
• Failure of conservative treatment, including at least 6 weeks of physical therapy directed at the affected joint(s).
• Not currently using NSAIDs and willing to avoid NSAIDs during the active treatment period, when clinically appropriate.
• Able to provide informed consent and to comply with study procedures and follow-up.

Additional eligibility for the Hyaluronic Acid (HA) alternative pathway - a participant may enter the HA pathway if ALL of the following apply, in addition to the inclusion criteria above:

• Has completed at least one regenerative medicine phase (dextrose, PRP, or doxycycline) and either

  1. was classified as an inadequate responder at the phase decision point (GPI < 40%) and declined further regenerative rotation,
  2. completed all available regenerative phases without adequate response, or
  3. experienced an adverse reaction during a regenerative phase that, in the investigator's judgment, contraindicates further regenerative treatment.
• A minimum waiting period of 4 weeks has elapsed since the last regenerative medicine treatment attempted, to allow resolution of post-injection effects before HA administration.
• The target joint(s) have clinical or imaging features amenable to HA viscosupplementation (e.g., articular/osteoarthritic pain component identifiable on examination or imaging).
• No contraindication to HA (see Exclusion Criteria).

Exclusion Criteria:

• Impaired decision-making capacity that precludes valid informed consent.
• Active local or systemic infection.
• Known allergy or contraindication to study injections, local anesthetics, iodinated contrast (if fluoroscopy is planned), or required procedural materials.
• Known hypersensitivity or intolerance to tetracycline-class antibiotics, including doxycycline (relevant to the doxycycline treatment phase).
• Mast cell activation syndrome (MCAS) or other mast cell disorder that, in the investigator's judgment, elevates the risk of injection-related hypersensitivity or systemic reactions.
• Active autoimmune or systemic inflammatory connective-tissue disease that, in the investigator's judgment, may confound the response to regenerative treatment or increase procedural risk.
• Known hypersensitivity to sodium hyaluronate or to the specific HA product to be used (Visco-3); active skin disease or infection over the planned injection site; venous or lymphatic stasis in the limb of the planned injection.
• Active malignancy or anticancer treatment within the prior 12 months; a prior malignancy in documented remission may be enrolled at the investigator's discretion with documented rationale.
• Uncontrolled diabetes mellitus, defined as HbA1c ≥ 8.5% on the most recent value within the prior 3 months; the investigator may also exclude for other objectively documented diabetes-related procedural or healing risk.
• Prior joint replacement at the target joint.
• Planned surgery during study participation.
• Corticosteroid injection to the target joint(s) within the prior 6 weeks.
• Concurrent enrollment in another interventional study for the same pain condition.
• Active litigation or disability claim related to the target condition (to limit secondary-gain confounding of self-reported outcomes).
• Pregnancy, or unwillingness to undergo pregnancy testing when fluoroscopy is planned (persons of childbearing potential).
• Inability to comply with study procedures or follow-up.